The role of MMP-1 in breast cancer growth and metastasis to the brain in a xenograft model

BMC Cancer

Hui Liu²  Yukinari Kato²  Stephanie A Erzinger²  Galina M Kiriakova²  Yongzhen Qian¹  Diane Palmieri¹  Patricia S Steeg¹  Janet E Price² 

[1] Women’s Cancers Section, Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, MD, 20892, USA

[2] Department of Cancer Biology, The University of Texas, M. D. Anderson Cancer Center, Houston, TX, 77030, USA

关键词: EGFR;    TGFα;    MMP-1;    Brain metastasis;    Breast cancer;   

Others  :  1080031
DOI  :  10.1186/1471-2407-12-583

 received in 2012-08-17, accepted in 2012-11-26,  发布年份 2012

【 摘 要 】

Background

Brain metastasis is an increasingly common complication for breast cancer patients; approximately 15– 30% of breast cancer patients develop brain metastasis. However, relatively little is known about how these metastases form, and what phenotypes are characteristic of cells with brain metastasizing potential. In this study, we show that the targeted knockdown of MMP-1 in breast cancer cells with enhanced brain metastatic ability not only reduced primary tumor growth, but also significantly inhibited brain metastasis.

Methods

Two variants of the MDA-MB-231 human breast cancer cell line selected for enhanced ability to form brain metastases in nude mice (231-BR and 231-BR3 cells) were found to express high levels of matrix metalloproteinase-1 (MMP-1). Short hairpin RNA-mediated stable knockdown of MMP-1 in 231-BR and 231-BR3 cells were established to analyze tumorigenic ability and metastatic ability.

Results

Short hairpin RNA-mediated stable knockdown of MMP-1 inhibited the invasive ability of MDA-MB 231 variant cells in vitro, and inhibited breast cancer growth when the cells were injected into the mammary fat pad of nude mice. Reduction of MMP-1 expression significantly attenuated brain metastasis and lung metastasis formation following injection of cells into the left ventricle of the heart and tail vein, respectively. There were significantly fewer proliferating cells in brain metastases of cells with reduced MMP-1 expression. Furthermore, reduced MMP-1 expression was associated with decreased TGFα release and phospho-EGFR expression in 231-BR and BR3 cells.

Conclusions

Our results show that elevated expression of MMP-1 can promote the local growth and the formation of brain metastases by breast cancer cells.

【 授权许可】

   
2012 Liu et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Weil RJ, Palmieri DC, Bronder JL, et al.: Breast cancer metastasis to the central nervous system. Am J Pathol 2005, 167:913-920.
• [2]Lin NU, Winer EP: Brain metastases: the HER2 paradigm. Clin Cancer Res 2007, 13:1648-1655.
• [3]Palmieri D, Fitzgerald D, Shreeve SM, et al.: Analyses of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis. Mol Cancer Res 2009, 7:1438-1445.
• [4]Bos PD, Zhang XH, Nadal C, et al.: Genes that mediate breast cancer metastasis to the brain. Nature 2009, 459:1005-1009.
• [5]Fidler IJ, Balasubramanian K, Lin Q, et al.: The brain microenvironment and cancer metastasis. Mol Cells 2010, 30:93-98.
• [6]Kim LS, Huang S, Lu W, et al.: Vascular endothelial growth factor expression promotes the growth of breast cancer brain metastases in nude mice. Clin Exp Metastasis 2004, 21:107-118.
• [7]Yoneda T, Williams PJ, Hiraga T, et al.: A bone-seeking clone exhibits different biological properties from the MDA-MB-231 parental human breast cancer cells and a brain-seeking clone in vivo and in vitro. J Bone Miner Res 2001, 16:1486-1495.
• [8]Ala-aho R, Kahari VM: Collagenases in cancer. Biochimie 2005, 87:273-286.
• [9]Murray GI, Duncan ME, O'Neil P, et al.: Matrix metalloproteinase-1 is associated with poor prognosis in colorectal cancer. Nat Med 1996, 2:461-462.
• [10]Murray GI, Duncan ME, O'Neil P, et al.: Matrix metalloproteinase-1 is associated with poor prognosis in oesophageal cancer. J Pathol 1998, 185:256-261.
• [11]Nakopoulou L, Giannopoulou I, Gakiopoulou H, et al.: Matrix metalloproteinase-1 and −3 in breast cancer: correlation with progesterone receptors and other clinicopathologic features. Hum Pathol 1999, 30:436-442.
• [12]Ito T, Ito M, Shiozawa J, et al.: Expression of the MMP-1 in human pancreatic carcinoma: relationship with prognostic factor. Mod Pathol 1999, 12:669-674.
• [13]McGowan PM, Duffy MJ: Matrix metalloproteinase expression and outcome in patients with breast cancer: analysis of a published database. Ann Oncol 2008, 19:1566-1572.
• [14]Poola I, DeWitty RL, Marshalleck JJ, et al.: Identification of MMP-1 as a putative breast cancer predictive marker by global gene expression analysis. Nat Med 2005, 11:481-483.
• [15]Pardo A, Selman M: MMP-1: the elder of the family. Int J Biochem Cell Biol 2005, 37:283-288.
• [16]Pei D: Matrix metalloproteinases target protease-activated receptors on the tumor cell surface. Cancer Cell 2005, 7:207-208.
• [17]McCawley LJ, Matrisian LM: Matrix metalloproteinases: they're not just for matrix anymore! Curr Opin Cell Biol 2001, 13:534-540.
• [18]Egeblad M, Werb Z: New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002, 2:161-174.
• [19]Iida J, McCarthy JB: Expression of collagenase-1 (MMP-1) promotes melanoma growth through the generation of active transforming growth factor-beta. Melanoma Res 2007, 17:205-213.
• [20]Hotary KB, Allen ED, Brooks PC, et al.: Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell 2003, 114:33-45.
• [21]Blackburn JS, Brinckerhoff CE: Matrix metalloproteinase-1 and thrombin differentially activate gene expression in endothelial cells via PAR-1 and promote angiogenesis. Am J Pathol 2008, 173:1736-1746.
• [22]Lu X, Wang Q, Hu G, et al.: ADAMTS1 and MMP1 proteolytically engage EGF-like ligands in an osteolytic signaling cascade for bone metastasis. Genes Dev 2009, 23:1882-1894.
• [23]Lev DC, Kiriakova G, Price JE: Selection of more aggressive variants of the gI101A human breast cancer cell line: a model for analyzing the metastatic phenotype of breast cancer. Clin Exp Metastasis 2003, 20:515-523.
• [24]Palmieri D, Bronder JL, Herring JM, et al.: Her-2 overexpression increases the metastatic outgrowth of breast cancer cells in the brain. Cancer Res 2007, 67:4190-4198.
• [25]Overall CM, Lopez-Otin C: Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat Rev Cancer 2002, 2:657-672.
• [26]Page-McCaw A, Ewald AJ, Werb Z: Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 2007, 8:221-233.
• [27]Huang SHF-J, Chou P-C, Sawaya R, Steeg PS: Inhibition of signal transducer and activator of transcription 3 activation suppresses the brain metastases of MDA-MB-231-BR cells in nude mice. Era of Hope DOD-BCPR meeting proceeding book 2008. page 273
• [28]Tsareva SA, Moriggl R, Corvinus FM, et al.: Signal transducer and activator of transcription 3 activation promotes invasive growth of colon carcinomas through matrix metalloproteinase induction. Neoplasia 2007, 9:279-291.
• [29]Milde-Langosch K, Roder H, Andritzky B, et al.: The role of the AP-1 transcription factors c-Fos, FosB, Fra-1 and Fra-2 in the invasion process of mammary carcinomas. Breast Cancer Res Treat 2004, 86:139-152.
• [30]Wyatt CA, Geoghegan JC, Brinckerhoff CE: Short hairpin RNA-mediated inhibition of matrix metalloproteinase-1 in MDA-231 cells: effects on matrix destruction and tumor growth. Cancer Res 2005, 65:11101-11108.
• [31]Eck SM, Hoopes PJ, Petrella BL, et al.: Matrix metalloproteinase-1 promotes breast cancer angiogenesis and osteolysis in a novel in vivo model. Breast Cancer Res Treat 2009, 116:79-90.
• [32]Heyn C, Ronald JA, Ramadan SS, et al.: In vivo MRI of cancer cell fate at the single-cell level in a mouse model of breast cancer metastasis to the brain. Magn Reson Med 2006, 56:1001-1010.
• [33]Fitzgerald DP, Palmieri D, Hua E, et al.: Reactive glia are recruited by highly proliferative brain metastases of breast cancer and promote tumor cell colonization. Clin Exp Metastasis 2008, 25:799-810.
• [34]De Luca A, Carotenuto A, Rachiglio A, et al.: The role of the EGFR signaling in tumor microenvironment. J Cell Physiol 2008, 214:559-567.
• [35]Ritter CA, Arteaga CL: The epidermal growth factor receptor-tyrosine kinase: a promising therapeutic target in solid tumors. Semin Oncol 2003, 30:3-11.
• [36]Zhang L, Sullivan P, Suyama J, Marchetti D: Epidermal growth factor-induced heparanase nucleolar localization augments DNA topoisomerase I activity in brain metastatic breast cancer. Mol Cancer Res 2010, 8:278-290.
• [37]Gril B, Palmieri D, Bronder JL, et al.: Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the brain. J Natl Cancer Inst 2008, 100:1092-1103.
• [38]Leker RR, Toth ZE, Shahar T, et al.: Transforming growth factor alpha induces angiogenesis and neurogenesis following stroke. Neuroscience 2009, 163:233-243.
• [39]Sharif A, Legendre P, Prevot V, et al.: Transforming growth factor alpha promotes sequential conversion of mature astrocytes into neural progenitors and stem cells. Oncogene 2007, 26:2695-2706.
• [40]White RE, Yin FQ, Jakeman LB: TGF-alpha increases astrocyte invasion and promotes axonal growth into the lesion following spinal cord injury in mice. Exp Neurol 2008, 214:10-24.
• [41]Lorger M, Felding-Habermann B: Capturing changes in the brain microenvironment during initial steps of breast cancer brain metastasis. Am J Pathol 2010, 176:2958-2971.
• [42]Lin Q, Balasubramanian K, Fan D, et al.: Reactive astrocytes protect melanoma cells from chemotherapy by sequestering intracellular calcium through gap junction communication channels. Neoplasia 2010, 12:748-754.
• [43]Zhang M, Olsson Y: Hematogenous metastases of the human brain–characteristics of peritumoral brain changes: a review. J Neurooncol 1997, 35:81-89.
• [44]Marchetti D, Li J, Shen R: Astrocytes contribute to the brain-metastatic specificity of melanoma cells by producing heparanase. Cancer Res 2000, 60:4767-4770.
• [45]Sierra A, Price JE, Garcia-Ramirez M, et al.: Astrocyte-derived cytokines contribute to the metastatic brain specificity of breast cancer cells. Lab Invest 1997, 77:357-368.
• [46]Trivedi V, Boire A, Tchernychev B, et al.: Platelet matrix metalloprotease-1 mediates thrombogenesis by activating PAR1 at a cryptic ligand site. Cell 2009, 137:332-343.
• [47]Yang E, Boire A, Agarwal A, et al.: Blockade of PAR1 signaling with cell-penetrating pepducins inhibits Akt survival pathways in breast cancer cells and suppresses tumor survival and metastasis. Cancer Res 2009, 69:6223-6231.
• [48]Kim YV, Di Cello F, Hillaire CS, Kim KS: Differential Ca2+ signaling by thrombin and protease-activated receptor-1-activating peptide in human brain microvascular endothelial cells. Am J Physiol Cell Physiol 2004, 286:C31-42.
• [49]Nicole O, Goldshmidt A, Hamill CE, et al.: Activation of protease-activated receptor-1 triggers astrogliosis after brain injury. J Neurosci 2005, 25:4319-4329.
• [50]Shibue T, Weinberg RA: Metastatic colonization: settlement, adaptation and propagation of tumor cells in a foreign tissue environment. Semin Cancer Biol 2011, 21:99-106.
• [51]Talmadge JE, Fidler IJ: AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Res 2010, 70:5649-5669.
• [52]Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM: Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol 2000, 18:1135-1149.
• [53]Roy R, Yang J, Moses MA: Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. J Clin Oncol 2009, 27:5287-5297.